One of the defense mechanisms against infection by both animals and plants is the production of peptides that have antimicrobial and antiviral activity. Various classes of these peptides have been isolated from tissues of both plants and animals. PCT application WO 95/03325 published Feb. 2, 1995 contains a review of the literature on this subject. Such peptides include tachyplesins, which are 17-18 amino acid peptides containing four invariant cysteines, the defensins, β-defensins, and insect defensins, which are somewhat longer peptides characterized by six invariant cysteines, and antifungal and antibacterial peptides and proteins which have been found in plants.
The applications in the series of which WO 95/03325 is a part provide a new class of antimicrobial and antiviral peptides, designated “protegrins”, representative members of which have been isolated from porcine leukocytes. These peptides are useful as antibacterial antiviral and antifungal agents in both plants and animals.
The isolation of some of the protegrin peptides was reported in a paper by Kokryakov, V. N. et al. FEBS (1993) 337:231-236 (July issue). A later publication described the presence of a new protegrin, whose sequence and that of its precursor were deduced from its isolated cDNA clone. Zhao, C et al, FEBS Letters (1994) 346:285-288. An additional paper disclosing cationic peptides from porcine neutrophils was published by Mirgorodskaya, O. A. et al. FEBS (1993) 330:339-342. Storici, P. et al. Biochem Biophys Res Comm (1993) 196:1363-1367, report the recovery of a DNA sequence which encodes a pig leukocyte antimicrobial peptide with a cathelin-like prosequence. The peptide is reported to be one of the protegrins. Additional publications related to protegrins are Harwig, S. S. L., et al. J Peptide Sci (1995) in press; Zhao, C., et al. FEBS Lett (1995) 376:130-134; Zhao, C. et al. FEBS Lett (1995) 368:197-202. See also, U.S. Pat. No. 5,464,823, U.S. Pat. No. 5,696,486, WO 95/03325, WO 96/37508 and WO 98/03192.
The protegrins have also been found to bind to endotoxins—i.e., the lipopolysaccharide (LPS) compositions derived from gram-negative bacteria which are believed responsible for gram-negative sepsis. The protegrins are also effective in inhibiting the growth of organisms that are associated with sexually transmitted diseases such as Chlamydia trachomatis and Neisseria gonorrhoeae.
The invention described below relates to peptide type compounds that are related to the protegrins described above, but reflect displacements of the protegrin cysteines at positions 6 and 15. The availability of these compounds, the preferred forms of which are designated parevins and tachytegrins, expands the repertoire of antimicrobial peptides and permits more exquisite matching of indications to antimicrobial formulations. Although at least one of C4, C5, C16 or C17 in the formula set forth below must be cysteine, the common name terminology of these components reflects particularly preferred situations wherein both of C4 and C17 are cysteine type residues (the tachytegrins) or where both C5 and C16 are cysteine type residues (the parevins).